Abstract

Metastatic spread of cancer cells from their primary site requires invasion into the vasculature, evasion at the distant organ site and colonization of the distant organ. Here we studied mechanisms of attachment and invasion into endothelial monolayers by cancer cells to identify driver molecules and signaling pathways that are crucial for the invasive and metastatic phenotype. In vitro studies were complemented by studies in zebrafish embryos and mouse models of cancer cell invasion and metastasis. In one approach we compared gene expression profiles across isogenic cell lines with distinct invasive behavior to identify candidate drivers and pathways. These were then subjected to functional validation. This comparison of gene expression profiles of isogenic cancer cell lines showed an upregulation of immune response cytokines associated with an endothelial invasive phenotype in human breast cancer cells. The role of the respective cytokine pathways was validated by blocking the respective receptors in in vitro assays and in a zebrafish metastasis model.